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Key Points Pathogenic bacteria evade host defences by subverting host signalling pathways in many different and sophisticated ways. An intriguing strategy used by several pathogens, mainly intracellular bacteria, is molecular or structural mimicry of host proteins. In the past few years, studies have revealed that some pathogenic bacteria secret specific proteins via their type 3 secretion systems (T3SSs) and type 4 secretion systems (T4SSs) to target host organelles. These proteins contain organelle localization signals that target the effectors, for example to the nucleus or the mitochondria. Legionella pneumophila , Chlamydia trachomatis and Burkholderia thailandensis secrete SET domain-containing proteins that encode histone methyltransferase activity to directly impose epigenetic changes on the chromatin landscape of the host cell, thus aiding bacterial intracellular replication. Listeria monocytogenes , pathogenic Escherichia coli strains and Shigella flexneri secrete specific effector proteins that change the levels of chromatin-binding proteins to indirectly alter the host chromatin to the advantage of the pathogen. Membrane dynamics, and in particular the eukaryotic secretory pathway, are targeted by bacterial pathogens to allow them to form a distinct replication-permissive vacuole inside the host cell. Legionella spp. and Brucella spp. target endoplasmic reticulum (ER)-derived vesicles and the retrograde traffic between the Golgi and the ER; Salmonella spp. and Chlamydia spp. interact with the trans -Golgi network or associated compartments. To target the ER or Golgi network, different secreted effectors evolved to specifically hijack RAB proteins and exploit phosphoinositide lipids, which are phosphorylated derivatives of phosphatidylinositol. Mitochondria are the power plants of the cell, but are also involved in essential cellular processes such as programmed cell death, calcium homeostasis, and the biosynthesis of amino acids, lipids and nucleotides. They also serve as hubs for innate immune signalling against viruses and bacteria. L. pneumophila , enteropathogenic E. coli , Vibrio cholerae and Anaplasma phagocytophilum have been reported to secrete diverse effectors that target mitochondria, mainly to inhibit inflammatory responses. Several bacterial pathogens have evolved the ability to subvert host cell functions. In this Review, Buchrieser and colleagues discuss the mechanisms used by bacteria to target eukaryotic organelles such as the nucleus, mitochondria, the endoplasmic reticulum and the Golgi apparatus, highlighting how these strategies potentiate bacterial infection. Many bacterial pathogens have evolved the ability to subvert and exploit host functions in order to enter and replicate in eukaryotic cells. For example, bacteria have developed specific mechanisms to target eukaryotic organelles such as the nucleus, the mitochondria, the endoplasmic reticulum and the Golgi apparatus. In this Review, we highlight the most recent advances in our understanding of the mechanisms that bacterial pathogens use to target these organelles. We also discuss how these strategies allow bacteria to manipulate host functions and to ultimately enable bacterial infection.

Legionella pneumophila is an intracellular bacterial pathogen that can cause a severe form of pneumonia in humans, a phenotype evolved through interactions with aquatic protozoa in the environment. Here, we show that L. pneumophila uses extracellular vesicles to translocate bacterial small RNAs (sRNAs) into host cells that act on host defence signalling pathways. The bacterial sRNA RsmY binds to the UTR of ddx58 (RIG-I encoding gene) and cRel , while tRNA-Phe binds ddx58 and irak1 collectively reducing expression of RIG-I, IRAK1 and cRel, with subsequent downregulation of IFN-β. Thus, RsmY and tRNA-Phe are bacterial trans-kingdom regulatory RNAs downregulating selected sensor and regulator proteins of the host cell innate immune response. This miRNA-like regulation of the expression of key sensors and regulators of immunity is a feature of L. pneumophila host-pathogen communication and likely represents a general mechanism employed by bacteria that interact with eukaryotic hosts. Legionella pneumophila expresses a range of bacterial determinants that mimic eukaryotic functions. Here the authors show small RNAs of L.pneumophila mimic eukaryotic microRNA and modulate the host response to infection.

Legionella pneumophila is an intracellular pathogen that causes a severe pneumonia called Legionnaires’ disease that is often fatal when not promptly diagnosed and treated. However, L. pneumophila is mainly an environmental pathogen of protozoa. This bacterium parasitizes free-living amoeba and other aquatic protozoa with which it co-evolved over an evolutionary long time. Due to the close relationship between hosts and pathogens, their co-evolution leads to molecular interactions such as the exchange of genetic material through horizontal gene transfer (HGT). Those genes that confer an advantage to the bacteria were fixed in their genomes and help these pathogens to subvert host functions to their advantage. Genome sequencing of L. pneumophila and recently of the entire genus Legionella that comprises over 60 species revealed that Legionellae have co-opted genes and thus cellular functions from their eukaryotic hosts to a surprisingly high extent never observed before for an prokaryotic organism. Acquisition and loss of these eukaryotic-like genes and eukaryotic domains is an ongoing process underlining the highly dynamic nature of the Legionella genomes. Although the large amount and diversity of HGT that occurred between Legionella and their protozoan hosts seems to be unique in the prokaryotic world, the analyses of more and more genomes from environmental organisms and symbionts of amoeba revealed that such genetic exchanges occur among all amoeba-associated bacteria and also among the different microorganisms that infect amoeba such as viruses. This dynamic reshuffling and gene-acquisition has led to the emergence of major human pathogens such as Legionella and may lead to the emergence of new human pathogens from the environment.

Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by the host surveillance system and to use the cell’s supplies to establish themselves. Indeed, certain pathogens have evolved proteins that imitate specific eukaryotic cell proteins, allowing them to manipulate host pathways, a phenomenon termed molecular mimicry. Bacterial “eukaryotic-like proteins” are a remarkable example of molecular mimicry. They are defined as proteins that strongly resemble eukaryotic proteins or that carry domains that are predominantly present in eukaryotes and that are generally absent from prokaryotes. Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by the host surveillance system and to use the cell’s supplies to establish themselves. Indeed, certain pathogens have evolved proteins that imitate specific eukaryotic cell proteins, allowing them to manipulate host pathways, a phenomenon termed molecular mimicry. Bacterial “eukaryotic-like proteins” are a remarkable example of molecular mimicry. They are defined as proteins that strongly resemble eukaryotic proteins or that carry domains that are predominantly present in eukaryotes and that are generally absent from prokaryotes. The widest diversity of eukaryotic-like proteins known to date can be found in members of the bacterial genus Legionella , some of which cause a severe pneumonia in humans. The characterization of a number of these proteins shed light on their importance during infection. The subsequent identification of eukaryotic-like genes in the genomes of other amoeba-associated bacteria and bacterial symbionts suggested that eukaryotic-like proteins are a common means of bacterial evasion and communication, shaped by the continuous interactions between bacteria and their protozoan hosts. In this review, we discuss the concept of molecular mimicry using Legionella as an example and show that eukaryotic-like proteins effectively manipulate host cell pathways. The study of the function and evolution of such proteins is an exciting field of research that is leading us toward a better understanding of the complex world of bacterium-host interactions. Ultimately, this knowledge will teach us how host pathways are manipulated and how infections may possibly be tackled.

Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (T H 2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings. ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.

is a gram-negative bacterium that inhabits freshwater ecosystems, where it is present in biofilm or as planktonic form. is mainly found associated with protozoa, which serve as protection from hostile environments and as replication niche. If inhaled within aerosols, is also able to infect and replicate in human alveolar macrophages, eventually causing the Legionnaires' disease. The transition between intracellular and extracellular environments triggers a differentiation program in which metabolic as well as morphogenetic changes occur. We here describe the current knowledge on how the different developmental states of this bacterium are regulated, with a particular emphasis on the stringent response activated during the transition from the replicative phase to the infectious phase and the metabolic features going in hand. We propose that the cellular differentiation of this intracellular pathogen is closely associated to key metabolic changes in the bacterium and the host cell, which together have a crucial role in the regulation of virulence.

FIC proteins regulate molecular processes from bacteria to humans by catalyzing post-translational modifications (PTM), the most frequent being the addition of AMP or AMPylation. In many AMPylating FIC proteins, a structurally conserved glutamate represses AMPylation and, in mammalian FICD, also supports deAMPylation of BiP/GRP78, a key chaperone of the unfolded protein response. Currently, a direct signal regulating these FIC proteins has not been identified. Here, we use X-ray crystallography and in vitro PTM assays to address this question. We discover that Enterococcus faecalis FIC (EfFIC) catalyzes both AMPylation and deAMPylation and that the glutamate implements a multi-position metal switch whereby Mg 2+ and Ca 2+ control AMPylation and deAMPylation differentially without a conformational change. Remarkably, Ca 2+ concentration also tunes deAMPylation of BiP by human FICD. Our results suggest that the conserved glutamate is a signature of AMPylation/deAMPylation FIC bifunctionality and identify metal ions as diffusible signals that regulate such FIC proteins directly. In many AMPylating FIC proteins a structurally conserved glutamate represses AMPylation. Here, the authors show that this glutamate supports deAMPylation in Enterococcus faecalis FIC (EfFIC), and that EfFIC switches from AMPylation to deAMPylation by binding Ca 2+ at distinct sites.

Legionella pneumophila, the causative agent of Legionnaires’ disease, a severe pneumonia, injects via a type 4 secretion system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here. we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δ ψ m ) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial F O F 1 -ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δ ψ m , preserves mitochondrial polarization, and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that Lp Spl is partially involved in conserving the Δ ψ m , but not LncP and MitF. The inhibition of the L. pneumophila -induced ‘reverse mode’ of the F O F 1 -ATPase collapsed the Δ ψ m and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δ ψ m and showed delayed cell death. This direct manipulation of the mode of activity of the F O F 1 -ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.

Legionella pneumophila replicates intracellularly by secreting effectors via a type IV secretion system. One of these effectors is a eukaryotic methyltransferase (RomA) that methylates K14 of histone H3 (H3K14me3) to counteract host immune responses. However, it is not known how L. pneumophila infection catalyses H3K14 methylation as this residue is usually acetylated. Here we show that L. pneumophila secretes a eukaryotic-like histone deacetylase (LphD) that specifically targets H3K14ac and works in synergy with RomA. Both effectors target host chromatin and bind the HBO1 histone acetyltransferase complex that acetylates H3K14. Full activity of RomA is dependent on the presence of LphD as H3K14 methylation levels are significantly decreased in a ∆lphD mutant. The dependency of these two chromatin-modifying effectors on each other is further substantiated by mutational and virulence assays revealing that the presence of only one of these two effectors impairs intracellular replication, while a double knockout (∆ lphD ∆ romA ) can restore intracellular replication. Uniquely, we present evidence for “para-effectors”, an effector pair, that actively and coordinately modify host histones to hijack the host response. The identification of epigenetic marks modulated by pathogens has the potential to lead to the development of innovative therapeutic strategies to counteract bacterial infection and strengthening host defences. Legionella pneumophilia is known to secrete more than 300 effectors via a type IV secretion system. Here, Schator et al. characterise how the chromatin modifying effectors RomA and LphD work synergistically to hijack host responses and facilitate bacterial replication.

Bacterial pathogens have developed many different strategies to hijack host cell responses to promote their own survival. The manipulation of lipid biogenesis and cell membrane stability is emerging as a key player in bacterial host cell control. Indeed, many bacterial pathogens such as Legionella, Pseudomonas, Neisseria, Staphylococci, Mycobacteria, Helicobacter , or Clostridia are able to manipulate and use host sphingolipids during multiple steps of the infectious process. Sphingolipids have long been considered only as structural components of cell membranes, however, it is now well known that they are also intracellular and intercellular signaling molecules that play important roles in many eukaryotic cell functions as well as in orchestrating immune responses. Furthermore, they are important to eliminate invading pathogens and play a crucial role in infectious diseases. In this review, we focus on the different strategies employed by pathogenic bacteria to hijack the sphingolipid balance in the host cell to promote cellular colonization.